Traumatic brain injury (TBI) is a common disorder with an actual incidence of over 1.7 million new cases a year (Faul et al, Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002-2006, Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Atlanta, Ga. Available at http://www.cdc.gov/Traumatic Brain Injury/). TBI affects both genders across all age groups and can cause both short term and long term disabilities. In 2011, the Department of Defense (DoD) asked the Institutes of Medicine (IOM) to convene an expert committee to review the potential role of nutrition in the treatment and resilience against TBI. The IOM report (Nutrition and Traumatic Brain injury, available at www.iom.edu/tbinutrition) explored the subject of nutrition and TBI and proposed certain areas of nutrition research that are promising in terms of treatment for the disorder. The IOM committee identified one promising solution that can immediately improve treatment efforts, namely early feeding of diets adequate in their level of energy and protein. The committee also suggested that more research be conducted to target potential nutritional interventions that fall into restoration of cellular energy processes, reduction in oxidative stress and inflammation, and recovery of brain function. The committee emphasized the importance of nutritional research to deal with TBI which, in one estimate 10-20% of returning veterans have sustained the disorder, while another estimate suggests that TBI accounts for up to one-third of combat related injuries. When civilian cases of TBI are added, the total number of TBI is indeed staggering.
Since the IOM Committee Report was published, a whole series of research publications have appeared to indicate that ketone bodies are useful in the treatment of neurodegenerative diseases such as Alzheimer's Parkinson's disease, amylotrophic lateral Sclerosis (ALS) and epilepsy. In order to achieve levels of plasma ketones that are therapeutic (2 mM to 7 mM) but not so high so as to produce acidosis, various investigators utilized the ketogenic diet or starvation to achieve “physiologic” or “therapeutic” ketosis (i.e. plasma ketone levels within the levels within the 2 mM to 7 mM range. The uses of the ketogenic diet(s) to treat neurodegenerative disorders are discussed in a recent review by Hashim and Van Itakkie (Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester, J Lipid Res. 55:1818-1926, 2014). Another ester of beta-hydroxybutyrate (R-3-hydroxybutyl R-3-hydroxybutyrate) was studied as an oral supplement to induce therapeutic ketosis in healthy adult subjects (Clarke, et al., Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects, Regul Toxicol Pharmacol 63:401-408, 2012), and later used to treat a patient with Alzheimer's disease, with noticeable improvements in symptoms (Newport et al, A new way to produce hyperketonemia: Use of ketone ester in a case of Alzheimer's disease. Alzheimer's and Dementia 2014:1-5, Elsevier) without resort to the ketogenic diet or carbohydrate caloric restriction.
The role of ketone body metabolism in TBI was first studied in experimental animals. There is evidence that administration of a ketogenic diet immediately after the first concussive injury (injury that produces no cell loss) improves cognitive function after the second concussive injury (Salame, et al, Ketogenic neuroprotection of repeat TBI in juvenile rats, Soc Neurotrauma 2012). In the same study, rats receiving the ketogenic diet for the 24 hr interval between the two concussive injuries showed better cognitive performance. Thus, based on this reference, one would understand that carbohydrate restriction in connection with elevated ketone levels is desired and failure to restrict carbohydrate intake is contraindicated. Further, in Gasior et al. (Neuroprotective and disease-modifying effects of the ketogenic diet, Behav. Pharmacol. 2006 Sep. 17(5-6) 431-439), the authors note that the beneficial effects in treating epilepsy with a ketogenic diet were quickly reversed when a high carbohydrate meal was introduced.
In TBI, there is disruption of glucose metabolism by the brain characterized by a decrease in glucose uptake, decreased glycolysis, increased glucose use by the phosphate pathway, decreased ATP production, and increased oxidative damage. Providing ketones for the brain to use (through starvation, the ketogenic diet(s), or ketone ester administration) results in a more rapid entry of the ketones into the tricarboxylic acid (TCA) cycle, a decrease in mitochondrial free radical production, an increased energy production via ATP, and increased glutathione peroxidase activity. Thus, the availability of ketone bodies in TBI compensates for the loss of energy resulting from TBI-induced diminished energy production from glucose. That the brain takes up ketones and utilizes them after controlled TBI has been demonstrated. Intravenous infusions of 14C-3-beta-hydroxybutyrate three hours following controlled concussive injury (CCI) in adult rats resulted in a greater cerebral uptake of the ketone with greater production of 14CO2 and ATP (Prins, et al; Increased cerebral uptake and oxidation of exogenous beta HB improves ATP following traumatic brain injury, J. Neurochem 90: 666-672, 2004). A 1996 article (Ritter, et al, Evaluation of a carbohydrate-free diet for patients with severe head injury, J Neurotrauma 13: 473-485, 1996) reviews a variety of animal models of TBI that have benefited from caloric deprivation or a ketogenic diet. The authors state that clinical trials are sorely needed in view of the extensive preclinical evidence that the ketogenic diet that induces hyperketonemia (up to 7 mM) is effective in treating TBI thus rendering ketone bodies available for the brain. In a study involving 20 adult patients with severe TBI, the patients were randomized to receive either standard enteral feed or a ketogenic diet (Ritter 1996, above). Those receiving the ketogenic diet demonstrated higher ketone body levels, lower blood lactate, and better-urinary nitrogen balance. The authors noted that the ketogenic diet was associated with consistent euglycemia whereas several episodes of hyperglycemia occurred in the group receiving the standard nutritional diet. Hyperglycemia has been associated with poorer outcome in patients with TBI, implying that the ketogenic diet was protective of hyperglycemia.
In a recent “thematic” review (Prins, et al, The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury, J Lipid Res 55: 2450-2457, 2014), the authors call for further studies to determine the optimal method to induce cerebral ketone metabolism in post injury brain. In this review the authors emphasize an initial surge in glucose metabolism soon after TBI, followed by a prolonged period of glucose metabolic depression. Ketones are the only endogenous fuel that can contribute significantly to energy production during a period of depressed glucose-derived energy. The resulting inability of the injured neurons to utilize the glucose results in homeostatic signals being generated to produce additional glucose from glycogen and also to produce additional insulin for suitable cell uptake, but the injured neurons still can't use either, so that hyperglycemia is persistent in the post injury condition.
In summary, there is extensive evidence for the beneficial role of ketogenic diet in TBI, particularly in experimental animals. However, unlike other conditions in which the use of ketogenic diets, starvation and the use of esters that are ketogenic, where glucogenic caloric intake is of no concern, the persistent hyperglycemia shown to be present in TBI, and the association of poorer outcomes in TBI the greater the hyperglycemia, leave only the ketogenic diet and starvation as the only diet driven treatments. Notwithstanding the above, Rainero et al, Insulin sensitivity is impaired in patients with migraine, Cephalagia 25:593-597, 2005, reported on twins with a high frequency of migraine headaches who improved during a ketogenic diet. The authors hypothesize the pathogenesis of migraine headache to diminished insulin sensitivity in the brain with consequent diminished utilization of glucose as a source of energy. Rainero states: “Our data show that insulin sensitivity is impaired in migraine and suggest a role for insulin resistance in the comorbidity between migraine and vascular disease.” Rainero however shows only a coincidence of diminished glucose utilization in the brain, but not any issue of hyperglycemia that needs to be contended with.
The ketogenic diet involves severe restriction of carbohydrates and includes a high proportion of fats. As cited by Gasior et al. in Neuroprotective and disease-modifying effects of the ketogenic diet, Behav. Pharmacol. 2006 Sep. 17(5-6) 431-439), the first ketogenic diet was published in 1921 by Wilder (The effects of ketonemia on the course of epilepsy, Mayo Bull 2:307-308, 1921) relating to the treatment of children with epilepsy that is resistant to the then available pharmacologic therapies. In terms of energy distribution, the original ketogenic diet was 90% fat, 8% protein, and 2% carbohydrate.
The ketogenic diet mimics the metabolic state of total starvation. Both result in hyperketonemia of approximately the same degree, with blood ketone body levels of 2-7 mM (Cahill, President's address: Starvation; Trans Am Clin Climatol Assoc, 94:1-21, 1983). It is important to emphasize that this degree of hyperketonemia is fully buffered in the circulation, does not induce acidosis, and has been termed as “physiologic” or “therapeutic” ketosis (Hashim, et al; Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester; J Lipid Res 44:1818-1826, 2014).
The ketogenic diet is not the most pleasant of diets. It is rather difficult to follow, and when followed, it can produce rises in LDL cholesterol, in uric acid, and free fatty acids. Occasionally, the ketogenic diet may result in increased incidence of nephrolithiasis and other serious complications (Van Itallie, et al; Ketone metabolism's ugly duckling; Nutr Rev. 61:327-341, 2003). Some of these adverse effects can be prevented by ensuring adequate hydration; and the hyperlipidemia can be avoided by boosting the proportion of polyunsaturated and monounsaturated fats in the diet (Fuehrlein et al Differential metabolic effects of saturated versus polyunsaturated fats in ketogenic diets; J Clin Endocrinol Metab 89:1641-1645, 2004). Also, the inclusion of medium-chain triglycerides (glycerol esters of fatty acids having typically 8 and/or 10 carbons in the fatty acid groups) into the ketogenic diet may improve the tolerability of the ketogenic diet (Huttenlocher et al; Medium-Chain triglycerides as a therapy for intractable childhood epilepsy, Neurology, Vol 11, November 1971, pp 1097-1103; Wu et al, Medium-Chain Triglycerides in infant Formulas and their Relation to Plasma Ketone Body Concentrations, Pediatric Research, Vol 20, No. 4, pp 338-341, 1986; Balietti et al, Ketogenic diets: An historical antiepileptic therapy with promising potentialities for the aging brain, Aging Research, and Reviews 9 (2010) 273-279.
Thus, while raising ketone levels in the TBI patient is desirable, one is left with the, unsuitable alternatives of use of the ketogenic diet or starvation as the choices for dietary intervention in TBI, a treatment choice which is difficult to maintain in TBI patients.